The diabetes gene Hhex maintains δ-cell differentiation and islet function (original) (raw)

1. Lindsay B. McKenna1,
2. Clifford W. Bogue2 and
3. Klaus H. Kaestner1,3
4. 1Department of Genetics and Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA;
5. 2Department of Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510, USA

Abstract

The homeodomain transcription factor HHEX (hematopoietically expressed homeobox) has been repeatedly linked to type 2 diabetes mellitus (T2DM) using genome-wide association studies. We report here that within the adult endocrine pancreas, Hhex is selectively expressed in the somatostatin-secreting δ cell. Using two mouse models with Hhex deficiency in the endocrine pancreas, we show that Hhex is required for δ-cell differentiation. Decreased somatostatin levels in _Hhex_-deficient islets cause disrupted paracrine inhibition of insulin release from β cells. These findings identify Hhex as the first transcriptional regulator specifically required for islet δ cells and suggest compromised paracrine control as a contributor to T2DM.

• diabetes
• transcription factors
• somatostatin
• pancreatic islet
• δ cell

Footnotes

• ↵3 Corresponding author
  E-mail kaestner{at}mail.med.upenn.edu

• Supplemental material is available for this article.

• Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.235499.113.

• Received November 26, 2013.

• Accepted March 17, 2014.

• © 2014 Zhang et al.; Published by Cold Spring Harbor Laboratory Press

This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genesdev.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.